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Development of a Robust and Highly Selective Ru(II)-Catalyzed Dynamic Kinetic Resolution Used to Manufacture AMG 232

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journal contribution
posted on 17.04.2020, 22:03 by Austin G. Smith, Matthew M. Bio, John T. Colyer, Khalid Diker, Gilles Gorins, Siân C. Jones, Maria Silva Elipe, Jason S. Tedrow, Shawn D. Walker, Seb Caille
We describe herein the development of a scalable Noyori reductive dynamic kinetic resolution to manufacture DLAC, a Δ-lactone precursor to the active pharmaceutical ingredient AMG 232. Central to this work was the identification of the ruthenabicyclic complex RuCl­[(S)-daipena]­[(S)-xylBINAP] ((S)-RUCY-xylBINAP), which afforded the product with >98:2 enantiomeric ratio at a substrate to catalyst loading (S/C) of 2000:1. By transesterification to a more sterically hindered isopropyl ester prior to the hydrogenation, we were able to curb unexpected ester reduction. Optimization of base equivalents in the final alkylation step to form DLAC prevented product degradation. The optimized process was scaled to >200 kg, providing 147 kg of DLAC in 56% overall yield with 99.9% optical purity.